Gene sequencing limited as disease predictor

If current trends continue, the cost of having one's genome analyzed will be comparable to that of the weekly supermarket bill. But will this give us the ability to predict which common diseases are likely to afflict us in the future? Well, according to a new study of twins that was published this week in Science Translational Medicine, the answer in most cases is likely to be no. In fact, the Johns Hopkins researchers warn of complacency, especially with respect to negative results; they could inadvertently give people a false sense of security. This is because while a positive test for a gene variant known to cause a disease means you may well be able to predict what the higher risk of developing the disease might be, a negative test does not mean there is no risk. This is particularly the case where many cancers are concerned, said the researchers. Co-author Dr Kenneth Kinzler gave the example of ovarian cancer, one of the diseases they analyzed in the study. Kinzler, who is co-director of the Ludwig Center at Johns Hopkins and professor of oncology, said in a statement: "As many as two percent of women undergoing whole genome sequencing could receive a positive test result for ovarian cancer, alerting them that they have at least a one-in-ten chance of developing that cancer over their lifetime." "The other 98 percent of women who receive a negative test for ovarian cancer will not be guaranteed a lifetime free of ovarian cancer because their risk of developing it is very similar to that of the general population," he added, pointing out: "So, a negative test is not a 'free pass' to discount the chance of acquiring any particular disease." The technology of whole genome sequencing allows scientists to catalogue all the genes that an individual inherits: including the variants from each parent. On average, if you were to compare any two individuals' genomes, using this technology you would find 4.5 million differences scattered throughout their DNA maps. The technology would allow you to pinpoint those differences, and link them to known or suspected risks of developing certain diseases. For the study, the researchers analyzed data on thousands of identical twins recorded in registries in Sweden, Denmark, Finland, Norway and the National Academy of Science's National Research Registry of World War II Veteran Twins. Identical twins have the same genome: they inherit the same variant of each gene from their parents. So, if the genome were the determining factor for common diseases, then you should be able to use the prevalence of disease in one twin to figure out how well genome sequencing could predict the risk of the disease developing in the other. Using mathematical models developed at Johns Hopkins and the Dana-Farber Cancer Institute, the researchers analyzed the incidence of 24 diseases among the pairs of twins they studied. These included cancers, autoimmune, genitourinary, neurological, cardiovascular, and obesity-associated diseases. The models calculated the capacity of whole genome sequencing to predict the risk of each disease based on typical thresholds used by doctors to begin preventive or therapeutic treatments. And what the researchers found was that while whole genome sequencing could, via a positive test result, warn people of an increased risk of at least one disease, most people would get negative results for the majority of diseases studied, thus failing to forewarn them of what they might develop later in life. The researchers suggest their findings cast doubt on whether whole genome sequencing can reliably predict most of the diseases that most of the people who will take such tests are likely to develop. Co-author Dr Bert Vogelstein said: "We believe that genomic tests will not be substitutes for current disease prevention strategies." Vogelstein, who is Clayton Professor of Oncology at the Johns Hopkins Kimmel Cancer Center, co-director of the Ludwig Center for Cancer Genetics, and investigator of the Howard Hughes Medical Institute, suggests that the key to cutting death rates to diseases will be things like: "Prudent screening, early diagnosis and prevention strategies, such as not smoking and removing early cancers." He and his colleagues conclude whole genome sequencing is likely to be informative in predicting cancer only in individuals with a strong family history of the disease. "In families with strong histories of cancer, whole genome sequencing can still be very informative for identifying inherited genes that increase cancer risk," says co-author Dr Victor Velculescu, a professor of oncology at Johns Hopkins, who with Vogelstein and Kinzler provided some of the early evidence that whole genome sequencing can identify inherited pancreatic cancer genes in families. "But hereditary cancers are rare. Most cancers arise from mutations acquired through environmental exposures, lifestyle choices and random mistakes in genes that occur when cells divide," he added. However, for four of the non-cancer diseases they studied, the researchers concluded that genetic tests could, in theory, identify more than three quarters of people who may develop them in the future: these are coronary heart disease in men, thyroid autoimmunity, type 1 diabetes and Alzheimer's disease.